tbuckley/cabot-search huggingface dataset:
Real-world outcomes with adjuvant nonsteroidal aromatase inhibitors (NSAIs) vs tamoxifen (TAM) in patients with hormone receptor−positive/human epidermal growth factor receptor 2−negative (HR+/HER2−) early breast cancer (EBC): A US database analysis.
Authors: Stephanie L. Graff, Sara M. Tolaney, Lowell L. Hart, Pedram Razavi, Peter A. Fasching, Wolfgang Janni, Lee S. Schwartzberg, Brad Lanoue, Tonatiuh Romero Salas, Aamir Khakwani, Courtney McDermott, Purnima Pathak, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2023)

542 Background: Randomized controlled trial (RCT) meta-analysis data have shown a significantly greater disease-free survival (DFS) benefit with aromatase inhibitors than TAM in patients with HR+/HER2− EBC. Here we compare real-world outcomes in patients with HR+/HER2− EBC who received adjuvant endocrine therapy (ET) with NSAIs or TAM. Methods: This was a retrospective analysis of ConcertAI’s deidentified electronic medical records data set of patients treated at US academic and community oncology clinics from January 1, 1995 to April 30, 2021. The cohort included patients with stage II-III (if IIIB or IIIC, confirmation was required on residual tumor status) HR+/HER2− EBC who underwent surgery and initiated adjuvant ET (excluding those who switched classes of ET); ovarian function suppression (OFS) was permitted. Menopausal status was determined using age (≥ 50 years) as a proxy for undocumented status. Invasive DFS (IDFS; risk of disease recurrence, death, or second primary tumor), distant DFS (DDFS; risk of distant recurrence, death, or second primary tumor), and overall survival (OS; risk of death) were assessed and defined as the time interval between start of ET and first event. Multivariate Cox regression analyses were performed, adjusting for age, stage, Charlson Comorbidity Index, and prior adjuvant or neoadjuvant chemotherapy for the ET cohort. Results: Of the total 3133 patients analyzed, 2507 were included in this analysis (NSAI ± OFS, n = 1854; TAM ± OFS, n = 653). Among these patients, the median (range) age was 59.5 (22.8-86.6) years, 25.4% were premenopausal, and 56.2% had tumor node involvement. The mean (SD) time to ET discontinuation was 46.2 (35.9) months overall and was similar between the NSAI and TAM cohorts. Reasons for ET discontinuation were undocumented or missing from the database for 76.8% of patients. Multivariate Cox regression analyses suggested a significant risk reduction with NSAIs vs TAM, with a 17% reduction in risk of an IDFS event (hazard ratio [HR], 0.83 [95% CI, 0.69-0.98]) and an 18% reduction in risk of a DDFS event (HR, 0.82 [95% CI, 0.69-0.98]). Although there were few events, OS analysis suggested a numerical trend favoring NSAIs over TAM, with a 12% reduction in risk of death (HR, 0.88 [95% CI, 0.69-1.13]). Conclusions: This real-world data analysis revealed a reduction in risk of IDFS and DDFS events with adjuvant NSAIs vs TAM in patients with HR+/HER2− EBC. Collectively, RCT and real-world data demonstrate greater benefit with adjuvant NSAIs vs TAM with respect to risk of recurrence in this patient population.
Clinical pathways innovation: A lesson on the value of clinician based feedback and collaboration with Flatiron Health.
Authors: Christopher Davella, Erin Mary Bange, Aditi Puri Singh, David W. Dougherty, Peter Edward Gabriel, Rebecca Lawrence Maniago, Jennifer Miao, Colin Harvey, Marcello Ricottone, Lawrence N. Shulman
Journal: Journal of Clinical Oncology (2023)

1578 Background: Clinical pathways have emerged as a strategy to provide value-based care by reducing treatment variation across oncology practice. Despite evidence for cost reduction and improved patient outcomes, adoption of clinical pathways has met resistance in the oncology community given concerns regarding the impact on workflow, and cost. Flatiron Assist, an EMR based pathways tool, is a promising solution to minimizing workflow friction by proving a novel, streamlined user interface. Methods: The Abramson Cancer Center at the University of Pennsylvania and Flatiron Health conducted a pilot study from August 2021-December 2022 to test the use of Flatiron Assist within its thoracic oncology practices. The goal of the pilot was to increase utilization as well as usability of the pathways tool over time through clinician and developer iterative collaboration. Penn’s clinical pathways were incorporated into the tool and integrated into the EMR. An education program trained clinicians on the tool’s functionality. Based on clinician feedback, the Penn team identified two areas of improvement for the tool: speed and organization of the tool keys and prompts. Changes made over time included: 1) increasing the speed of the tool 2) restructuring the organization of keys and prompts, and 3) creation of a “hot button” for three common clinical scenarios in order to increase efficiency. Speed of the application (session length in seconds), utilization of the hot button (number of sessions/overall sessions) and overall physician adoption (treatment ordering with Flatiron Assist/total thoracic orders) were calculated during the pilot. Results: Provider utilization of the pathways tool increased over time with a baseline adoption rate of 29% in August 2021 and a peak of 74% in April 2022. Median session length decreased over time from 106.4 seconds (August 2021) to 39.9 seconds (December 2022). Peak performance for session length was 38.2 seconds (November 2022). Usage of the hot button introduced in August 2022 has increased over time from 27.6% of sessions to 41.8 % in November 2022. Thoracic providers ordered, on average, 1.7 new treatment plans per week, resulting in less than 1.5 extra minutes of work per week with optimal use of the pathways tool. Conclusions: Collaboration between Penn and Flatiron Health effectively reduced specific areas of friction associated with the use of Flatiron Assist. Changes made to the speed, button organization and functionality of the tool contributed to increased clinician utilization over time. Future development of EMR based pathway tools should incorporate clinician engagement and feedback.
Discovery of CDK4/6 bifunctional degraders for ER+/HER2- breast cancer.
Authors: Hannah Majeski, Akinori Okano, Angela Pasis, Casey Carlson, Arvind Shakya, Shenlin Huang, Aparajita Hoskote Chourasia, Leah M. Fung, Qiao Liu
Journal: Journal of Clinical Oncology (2023)

1083 Background: CDK4/6 inhibitors (CDK4/6i) such as palbociclib and ribociclib are used to treat ER+/HER2- breast cancer, but patients can develop resistance via many mechanisms, several of which converge on the upregulation of CDK6. This has been shown to limit the effectiveness of CDK4/6i in ER+ breast cancer with up to 20% patients exhibiting innate resistance and up to 70% patients developing acquired resistance after 3 years on therapy (Scheidemann, 2021, doi:10.3390/ijms222212292). Methods: To address this limitation, we utilized our PRODEGY platform of Cereblon (CRBN) binders to synthesize CRBN mediated CDK4/6 bifunctional degraders to potently inhibit tumor growth for treatment of naïve ER+/HER2- breast cancer and CDK4/6i resistant tumors. Results: Target degradation by immunoblot analysis of the triple negative breast cancer (TNBC) cell line, MDA-MB-231, treated with our CDK4/6 bifunctional degraders for 6 hours showed up to 85% degradation of CDK4 and CDK6 with DC 50 s of 1-100nM. CDK4/6 phosphorylates the protein RB which releases the transcription factor E2F, inducing the expression of genes which promote cell cycle progression. Analysis of RB phosphorylation by in-cell western upon 24 hours of CDK4/6 degrader treatment showed phospho-RB IC 50 s at &lt;30nM. Cell cycle analysis by staining with propidium iodide after 24 hours of treatment with CDK4/6 degraders induced G0/G1 cell cycle arrest at concentrations as low as 10nM. We used a 2D colony formation assay (CFA) as a readout for inhibition of proliferation by cell cycle arrest. Our CDK4/6 degraders showed potent inhibition of cell proliferation with CFA IC 50 s of &lt;100nM in TNBC cell lines and &lt;25nM in ER+ cell lines, including MCF7, T47D and ZR751 compared to CDK4/6i which ranged from 200nM to 500nM in MCF7 cells. We demonstrated that our CDK4/6 bifunctional degraders were significantly more potent in vitro than the CDK4/6i ribociclib and palbociclib, and the increased activity was due to CRBN mediated target degradation. Our CDK4/6 bifunctional degraders display excellent pharmacokinetic properties in mice with half-lives between 2-10 hours, oral bioavailability between 50-96%. MCF7 xenograft results with our proof-of-concept CDK4/6 degrader showed dose-dependent tumor growth inhibition and greater potency compared to the clinical CDK4/6i ribociclib. We saw tumor regression with our degrader at higher doses which we did not see at any dose of CDK4/6i. Conclusions: Our CDK4/6 bifunctional degraders display excellent single agent activity in vitro and in vivo particularly in comparison to clinically approved CDK4/6i, indicating that using a degrader approach to targeting this pathway may be more effective than current inhibitor therapies.
Toward automating RECIST 1.1: Improving AI new lesion detection with longitudinal image data.
Authors: Amanda Gong, Morgan Daly, Gabriel Melendez-Corres, Pang Yu Teng, Tanmay Sanjay Hukkeri, Wahi-Anwar Muhammad, Kathleen Ruchalski, Jonathan Goldin, Matthew S. Brown
Journal: Journal of Clinical Oncology (2023)

e13545 Background: Automating RECIST 1.1 would offer benefits in speed, consistency, and cost of clinical trial imaging reads. Detection of new lesions is subjective and a common source of reader adjudication. Current AI lesion detection typically uses single timepoint images. The use of temporal data in AI is a rapidly evolving field in non-medical applications and new lesion detection in response assessment may benefit from longitudinal multi timepoint images. We explore the impact of longitudinal image input to deep neural networks for new lesion detection; as a proof of concept, we compare single vs dual timepoint input in new liver lesion detection in CT. Methods: We utilized CT images from two public datasets: 1) diseased liver (DL), a subset of DeepLesion (doi: 10.1117/1.JMI.5.3.036501), and 2) healthy liver (HL) from potential liver donors (Med Image Anal 69 (2021) 101950).. Due to the lack of a publicly available longitudinal image dataset with new lesions, we simulated (“sim”) a longitudinal study by registering HL scans (sim healthy baseline) with DL scans (sim follow up with new lesion) and selecting well-paired images using mutual information. From each pair of scans, we select one positive (with new lesion on follow up) and one negative (without lesion on follow up) 6x6cm image patch from within the liver, creating a dataset of 3296 patches with a balanced number of pos/neg samples. We trained two deep neural networks to classify the presence of a new liver lesion: 1) a conventional single timepoint model (ST) trained on DL patches only, i.e. using the follow up scan only, and 2) an experimental dual-timepoint model (DT) trained on patch pairs from DL-HL paired scans. We used 5-fold cross validation and paired t tests to compare model AUC and accuracy. Results: Of 10,594 CT studies (4,427 patients, pts) in DeepLesion, we paired 1648 DL scans (946 pts with liver lesions) with one of 20 registered HL scans (20 pts). The DT model outperformed the ST model, increasing AUC from 0.914 ± 0.002 to 0.929 ± 0.005 (p=0.040), with similar trends in accuracy (dataset split, Table 1). Conclusions: The DT model outperformed the ST model in the detection of new liver lesions, suggesting preliminary the benefit of multi-timepoint input to a deep neural network using sim longitudinal data. The use of longitudinal image data to improve interval change detection is a step towards automating radiologic response assessment in clinical trials. We plan to extend this work to automate new lesion detection in real clinical trial longitudinal images. Results (bold) are reported on test set across 5 folds. N image patches (ST) or patch pairs (DT). [Table: see text]
Estrogen receptor positive breast cancer in an Afro-Caribbean cohort.
Authors: Emanuela Cimpeanu, Alexander H Wu, Bo Lin, Mariam Azam, Ana M Ventura, Edwin Chiu, Evelyn Taiwo
Journal: Journal of Clinical Oncology (2023)

e12550 Background: Estrogen receptor-positive breast cancer (EBC) accounts for 78% of breast cancer (BC) cases in the United States, and with better prognosis compared to other BC subtypes. There is limited information on the incidence, presentation, and outcomes of BC in black women from the Caribbean. We describe the clinicopathologic features and treatment outcomes of EBC in this underrepresented immigrant patient population. Methods: This is a retrospective study conducted at Kings County Hospital, a public hospital in a Brooklyn, New York neighborhood with the second highest population of Afro-Caribbeans in the United States. Demographics and clinicopathological data of patients diagnosed with BC from 2015-2018 were collected from the hospital’s tumor registry. Descriptive statistics and Chi-square testing were used to analyze the data. Results: Of the 299 women with a BC diagnosis, 185 (62%) had EBC, with median age of 61, and median BMI of 29.9. Stratification by menopausal status revealed 75% of these patients were post-menopausal. 37% of pre-menopausal and 28% of post-menopausal women presented with lymph node involvement (LNI). At diagnosis, 61% of patients had localized disease, 30% regional LNI, and 9% distant metastases. Sub-analysis revealed 25%, 22%, 28%, 16% and 9% with stages 0, I, II, III and IV respectively. 39% of patients presented with Nottingham Grade 3, 50% with Grade 2, and 11% with Grade 1 disease. 25% of patients without LNI had Oncotype Dx testing. 22% of these had Recurrence Score (RS) less than 11, 50% RS 11-25, and 28% RS 26 or higher. Of the 27 patients who received neoadjuvant treatment, 22% had complete pathologic response, 37% had partial response, and 33% had disease progression. 81% of patients self-identified as Afro-Caribbean, 27% reported first- or second-degree relatives with a BC diagnosis and 22% first-degree relatives with non-breast malignancy. At time of data analysis, at median of 6 years, 75% of all patients were relapse and progression-free. Lasting response was correlated with cancer stage (p &lt; 0.01) but independent of tumor grade and Oncotype Dx RS (p = 0.18 and p = 0.29, respectively). Conclusions: In our study, Afro-Caribbean women with EBC presented with high-grade tumors and high incidence of regional LNI. Pre-menopausal women had a higher incidence of nodal involvement. Notable was a strong family history of cancer implying inherited or familial cancer syndromes. Progression-free survival was lower than expected and correlates with disease stage, but not with low Oncotype Dx RS. Further research is warranted to investigate better prognostic tools for this population.
Nomograms for predicting survival in patients with HER2 negative breast cancer.
Authors: Yiyue Xu, Bing Zou, Bingjie Fan, Butuo Li, Linlin Wang
Journal: Journal of Clinical Oncology (2023)

e12528 Background: It is increasingly recognized that there is considerable heterogeneity in HER2-negative breast cancer. The clinicopathological characteristics differed between HER2-low and HER2-0 breast cancer evaluated by immunohistochemistry (IHC) or in situ hybridization (ISH). HER2-low breast cancer may benefit from novel antibody-drug conjugates. However, the immunohistochemical agreement of HER2-low is poor. We aimed to construct nomograms to predict the survival of HER2-negative breast cancer and to evaluate the effects of HER2 on survival at the RNA transcript level. Methods: A retrospective analysis was performed on breast cancer patients who were evaluated HER2-negative by IHC or ISH in the TCGA database. Univariate and multivariate cox regression analysis was used to evaluate whether the HER2 RNA transcript level and clinical parameters were independent predictors for overall survival (OS), progression-free survival (PFS), and Disease-Specific Survival (DSS), and nomograms were generated for the prediction of 1-, 2-, 3-, 5-year OS, PFS, and DSS based on significant parameters. Survival curves were drawn using the Kaplan-Meier methods to compare mortality outcomes according to HER2 RNA transcript level (75% vs. 25%). Results: A total of 769 HER2-negative patients were included in the analysis. The median age of patients was 56 years (range 26-30), and the majority were White (80.3%). Univariate and multivariate cox regression analysis showed that age, pN_stage, and pM_stage were independent predictors for OS, but HER2 was not. The C-index of a nomogram based on these three parameters was 0.723 (95%CI, 0.6555-1). HER2, pT_stage, pN_stage, and pM_stage were analyzed as independent predictors of PFS. HER2, pN_stage, and pM_stage were independent predictors of DSS. The C-indexes of established nomograms were 0.734 (95%CI, 0.672-1) and 0.775 (95%CI, 0.686-1) respectively. PFS and DSS were significantly better for patients with high HER2 RNA transcript levels (PFS, log-rank p = 0.00446, HR = 0.352; DSS, log-rank p = 0.0119, HR = 0.247). Conclusions: In the TCGA database, the HER2 RNA transcript level was an independent predictor for PFS and DSS in HER2-negative breast cancer. Stratification of patients at the RNA level can help clinicians optimize treatment for HER2-negative breast cancer.
Use of PROMIS to capture patient reported outcomes over time for patients on I-SPY2.
Authors: Saya Jacob, Hongmei Yu, Denise M. Wolf, Aheli Chattopadhyay, Susie Brain, Carol Simmons, Kathryn Jean Ruddy, Irene Kang, Anne Hudson Blaes, Amrita B Somani, Dawn L. Hershman, Laura Esserman, Michelle E. Melisko
Journal: Journal of Clinical Oncology (2023)

611 Background: Patient reported outcomes (PROs) capture direct feedback from patients in clinical trials. The NIH Patient-Reported Outcomes Measurement Information System (PROMIS) is an open source and validated PRO platform. Data on PROMIS score trajectories over time for breast cancer patients undergoing neoadjuvant chemotherapy (NAC) are limited. Methods: We administered paper surveys to patients enrolled on the I-SPY2 trial, a multicenter, randomized phase 2 trial comparing novel agents to standard NAC in high-risk breast cancer. PRO domains included PROMIS Physical Function, Anxiety, Depression, Applied Cognition and Fatigue. Surveys were administered at baseline (post-consent), C1D1, inter-regimen (~12 wks into NAC), pre-surgery and at 1, 6, 12, and 24 months post-surgery. Responses were scored using the HealthMeasures Scoring Service to generate a standardized T score, with a score of 50 representing the general US population mean. Higher Anxiety, Depression and Fatigue scores represent worse symptoms; higher Physical Function and Applied Cognition scores represent better symptoms. We calculated average scores by time-point and compared changes from baseline to various grouped time points using a paired t-test. Results: From 1/2012 to 7/2020, 1631 patients enrolled in I-SPY 2 with 959 completing the baseline survey. 62% had at least two “on-treatment” surveys, and 52% had at least one follow-up time-point. Average baseline PROMIS scores for Physical Function, Anxiety, Depression, Applied Cognition and Fatigue were 46.7, 55.1, 47.2, 53.3 and 46.0 respectively. Between baseline and the latest on-treatment time point we observed improvement in Anxiety (-5.2) and worsening in Physical Function, Applied Cognition and Fatigue (-5.4, -6.9 and +8.2 respectively). Between baseline and the latest post-surgery time point, we saw improved Anxiety (-5.9) and worsened Physical Function, Applied Cognition and Fatigue (-5.9, -3.6 and +4.3). Depression changed minimally. Conclusions: Using PROMIS, patients on I-SPY2 experienced worse Physical Function, Applied Cognition and Fatigue but improved Anxiety during and after treatment compared to baseline. While changes in Applied Cognition and Fatigue recovered partially after treatment, Physical Function scores did not, suggesting potential for longer term impact on quality of life. Clinical trial information: NCT01042379 . [Table: see text]
Possible advantage of granulocyte colony-stimulating factor in breast cancer chemotherapy during COVID-19 pandemic: A single center experience in Japan.
Authors: Kioto Yokoyama
Journal: Journal of Clinical Oncology (2023)

e12505 Background: The COVID-19 pandemic seems to be ongoing in many countries, including Japan. ASCO and ESMO guidelines recommend treatment with during chemotherapy, and their use also reduces the risk of febrile neutropenia. On the other hand, there is a report that use of granulocyte colony-stimulating factor (G-CSF) increases the risk of admission and mortality due to COVID-19, so appropriate G-CSF use is still under discussion. Methods: Breast cancer patients treated with chemotherapy at our hospital from October 2020 to December 2022 were included in this study. We retrospectively collected patient data, including chemotherapy regimens, G-CSF use, COVID-19 infection, and COVID-19 severity, from electronic medical records. Results: Twenty-four patients (two bilateral breast cancers) received chemotherapy during this period. Twenty-three patients were female (95.8%) and one was male (4.2%), the mean age was 58.7 (34–79) years; 11 (45.8%) had early-stage breast cancer and 14 (58.3%) had advanced or recurrent breast cancer (one patient with early-stage breast cancer developed recurrent breast cancer during the study period). Seventeen cases (65.4%) were ER positive and nine cases (34.6%) were negative, 15 cases (57.7%) were PgR positive and 11 cases (42.3%) were negative, and six cases (23.1%) were HER2 positive and 20 cases (76.9%) were negative. The major chemotherapy regimens were ddAC in three patients (12.5%), AC in eight patients (33.3%), wPTX in 11 patients (45.8%), DTX in four patients (16.7%), TC in one patient (4.2%) and S-1 in eight patients (33.3%). Some patients also received treatment with anti-HER2 or anti-VEGF drugs or an immune check-point inhibitor but we did not consider these. Of the 13 patients who received AC, DTX and TC, 11 patients received PEG-GCSF in all their cycles. Among all patients receiving, COVID-19 symptoms were suspected on four occasions, and the COVID-19 antigen test was conducted, but all were negative, so no cases of COVID-19 were observed. Of the 46 cycles of AC, DTX, and TC, the proportion of patients with suspected COVID-19 symptoms who underwent antigen testing tended to be lower in the PEG-GCSF group (37 cycles) than in the no PEG-GCSF group (nine cycles) (2.7% vs. 22.2%; p = 0.0933, Fisher’s exact test). Conclusions: In this study, we did not find any cases of COVID-19 infection during chemotherapy, and so were unable to analyze the association between G-CSF use and COVID-19 infection severity. However, we did observe a trend toward a lower rate of potential COVID-19 with administration of PEG-GCSF. This might reflect a better quality of life for breast cancer chemotherapy patients.